The present invention relates to a therapeutic agent for various kinds of inflammatory disease.
It is known that various inflammatory diseases, rheumatoid diseases, immunoreactive diseases, cancer metastasis and viral diseases are caused by the abnormal production of inflammatory cytokines and matrix metalloprotease and also by the increase in the expression of inflammatory cell adhesion molecules.
Although various medicines for these diseases were developed in the prior art, further development of a medicine having a stronger efficiency, higher safety and weaker side effects is demanded.
The pathophysiological states of various chronic inflammatory diseases are considered to be caused by the continuous production of inflammation mediators such as cytokines particularly, inflammatory cytokines including IL-1, IL-2, IL-6, IL-8 and tumor necrosis factor (TNF)], adhesion molecules, tissue destroying enzymes (such as matrix metalloprotease), etc. by the continuous extracellular stimulation.
The inflammatory mediators are produced because the gene expression is activated by the extracellular stimulation. A substance having the most important role in this step is a transcription factor known as AP-1 or NF-kappa B. Namely, it is expected that when the activation of AP-1/NF-kappa B can be inhibited, the development of inflammation and the advance thereof into chronic stage can be prevented and that such a method will be a hopeful treatment of inflammatory diseases such as rheumatoid arthritis and various autoimmune diseases.
Glucocorticoid hormone (GC) which strongly inhibits the activation of intracellular AP-1 and NF-kappa B has been used as a powerful anti-inflammatory agent and immunosuppressant. However, the use of GC as a medicine is limited because it has various side effects due to hormonic action thereof and it causes rebound phenomenon.
An object of the present invention is to provide a new compound effective to cure chronic inflammatory disease with high activity and fewer side effects.
Another object of the present invention is to provide a pharmaceutical composition comprising corresponding new compound.
After intensive investigations made for the purpose of finding compounds having a strong activity of inhibiting the activation of AP-1 and NF-kappa B and useful as a strong remedy for chronic inflammatory diseases, the inventors have found that compounds of general formula (I) which will be described below have this effect. The present invention has been completed on the basis of this finding.
That is, the present invention provides a heterocyclic compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. 
wherein R1 is a cycloalkyl group, a cycloalkyl group having a substituent(s), a cycloalkenyl group or a cycloalkenyl group having a substituent(s); each R2 and R3 is a hydrogen atom or an alkyl group; R4 is an alkyl group, an alkyl group having a substituent(s), an alkenyl group, an alkenyl group having a substituent(s), a cycloalkyl group, a cycloalkyl group having a substituent(s), a cycloalkenyl group, a cycloalkenyl group having a substituent(s), an aryl group, an aryl group having a substituent(s), an aromatic heterocyclic group having at least one hetero-atom within a ring or an aromatic heterocyclic group having a substituent(s) and at least one hetero-atom within a ring; A is a heterocyclic ring or a heterocyclic ring having a substituent(s); B is an aromatic ring, an aromatic ring having a substituent(s), a heterocyclic ring or a heterocyclic ring having a substituent(s); n is an integer selected from 0 to 6; xe2x80x94Yxe2x80x94 is an interatomic bond, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94NR5xe2x80x94, xe2x80x94CSxe2x80x94NR6xe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 wherein each R5 and R6 is a hydrogen atom or an alkyl group; and xe2x80x94Xxe2x80x94 is an interatomic bond, xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHR7xe2x80x94, xe2x80x94CHR8xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CSxe2x80x94, xe2x80x94CSxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Sxe2x80x94CHR9xe2x80x94, xe2x80x94CHR10xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CSxe2x80x94, xe2x80x94CSxe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94NR11xe2x80x94, xe2x80x94NR12xe2x80x94SO2xe2x80x94, xe2x80x94NR13xe2x80x94, xe2x80x94NR14xe2x80x94CHR15xe2x80x94, xe2x80x94CHR16xe2x80x94NR17xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90NOR18)xe2x80x94, xe2x80x94C(xe2x95x90CHR19)xe2x80x94, xe2x80x94COxe2x80x94CHR20xe2x80x94, xe2x80x94CHR21xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR22xe2x80x94, xe2x80x94NR23xe2x80x94COxe2x80x94, xe2x80x94CR24R25xe2x80x94, xe2x80x94CHR26xe2x80x94CHR27xe2x80x94, xe2x80x94CR28xe2x95x90CR29xe2x80x94, xe2x80x94Oxe2x80x94CHR30xe2x80x94CHR31xe2x80x94 wherein each R7, R8, R9, R10, R15, R16, R20, R21, R24, R28, R29, R30 and R31 is either of a hydrogen atom or an alkyl group; each of R11, R12, R13, R14, R17, R18, R19, R22 and R23 is either of a hydrogen atom, an alkyl group or an acyl group; each of R26 and R27 is either of a hydrogen atom, a hydroxy group or an alkyl group; and R25 is a hydrogen atom, a hydroxy group, an alkyl group, an alkyl group having a substituent(s), a mercapto group, an alkoxy group, an alkylthio group, an acyloxy group, an amino group, an alkylamino group, an amino group substituted with an amino protective group, a carboxyl group, an alkoxycarbonyl group, an aminocarbonyl group, or a cyano group.
Further, the present invention provides an AP-1 or NF-kappaB activation inhibitor, an inflammatory cytokine production inhibitor, a matrix-metalloprotease production inhibitor and an inflammatory cell adhesion factor expression inhibitor, each of which comprises, as an active ingredient, the above-described heterocyclic compound or a pharmaceutically acceptable salt thereof, and these can be used as an anti-inflammatory agent, an anti-rheumatism agent, an immuno-suppressive agent, a cancer metastasis inhibitor, an antiviral agent or a curative agent for arterial sclerosis.
It is to be noted that a heterocyclic compound or a pharmaceutically acceptable salt thereof according to the present invention, in which R1 is a cycloalkyl group having a substituent(s), may be more effective. Among these, compounds wherein R1 is a cyclopropyl group having a substituent(s), more specifically either of a 2,2-dimethylcyclopropyl group or a 2,2-dichlorocyclopropyl group are of high activity. Among these, higher activity can be obtained by compounds wherein R4 is 2,2-dimethylcyclopropyl group or 2,2-dichlorocyclopropyl group, xe2x80x94Yxe2x80x94 is xe2x80x94COxe2x80x94 and n=0; or compounds wherein R4 is an aryl group or an aryl group having a substituent(s), xe2x80x94Yxe2x80x94 is xe2x80x94COxe2x80x94 and n=1; or compounds wherein R4 is an aryl group or an aryl group having a substituent(s), xe2x80x94Yxe2x80x94 is an interatomic bond and n is 1 or 2.
Examples of the halogen atom in the present invention include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The alkyl group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a tert-pentyl group, a neopentyl group, a 2-pentyl group, a 3-pentyl group, a n-hexyl group and a 2-hexyl group, wherein the methyl group and the ethyl group are preferable.
The alkenyl group means a straight-chain or branched-chain alkenyl group having 1 to 6 carbon atoms such as a 1-propenyl group, an allyl group, an isopropenyl group, a 1-butenyl group and a 2-butenyl group.
The cycloalkyl group means a cyclic alkyl group having 3 to 6 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, wherein the cyclopropyl group is a preferable cycloalkyl group.
The cycloalkenyl group means a cyclic alkenyl group having 3 to 6 carbon atoms such as a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group and a cyclohexenyl group.
The hetero atom means specifically, for example, an oxygen atom, a sulfur atom and a nitrogen atom, wherein nitrogen atom is preferable.
The an aryl group means specifically, for example, a phenyl group, an indenyl group, a naphthyl group and a fluorenyl group, wherein phenyl group is preferable.
The aromatic heterocyclic group having at least one hetero atom means specifically, for example, a pyranyl group, a pyridyl group, a pyridazyl group, a pyrimidyl group, a pyrazyl group, a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a triazolyl group, a tertazolyl group, a pyrazolyl group, a furazanyl group, a thiadiazolyl group and a indolyl group, wherein pyridyl group, pyrimidyl group, imidazolyl group and triazolyl group are preferable, and among them pyridyl group is more preferable.
The acyl group means a formyl group, an acyl group having a straight-chain, a branched-chain or a cyclic alkyl group having 1 to 6 carbon atoms or an acyl group having a substituted or unsubstituted aryl group, and specifically, it includes, for example, a formyl group, an acetyl group, a propionyl group, a butyloyl group, an isobutyloyl group, a valeloyl group, an isovaleloyl group, a pivaloyl group, a hexanoyl group, an acryloyl group, a metacryloyl group, a crotonoyl group, an isocrotonoyl group, a benzoyl group and a naphthoyl group.
The acyloxy group means a formyloxy group or an acyloxy group having a straight-chain, a branched chain or a cyclic alkyl group having 1 to 6 carbon atoms or an acyloxy group having an substituted or unsubstituted aryl group, and specifically, it includes, for example, a formyloxy group, an acetoxy group, a propionyloxy group, a butyloyloxy group, an isobutyloyloxy group, a valeloyloxy group, an isovaleloyloxy group, a pivaloyloxy group, a hexanoyloxy group, an acryloyloxy group, a metacryloyloxy group, a crotonoyloxy group, an isocrotonoyloxy group, a benzoyloxy group and a naphthoyloxy group.
The alkoxy group means an alkoxy group having a straight chain, a branched chain or a ring alkyl group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a cyclopropyloxy group, a cyclobutoxy group, a cyclopentyloxy group and a cyclohexyloxy group, wherein methoxy group and ethoxy group are preferable.
The alkylthio group means an alkylthio group having a straight-chain, a branched-chain or a ring alkyl group having 1 to 6 carbon atoms such as a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a n-butylthio group, a isobutylthio group, a sec-butylthio group, a tert-butylthio group, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group and a cyclobutylthio group.
The alkylamino group means an amino group mono-substituted or bi-substituted with alkyl group, the alkyl group including those having been specified in above description of the xe2x80x9calkyl groupxe2x80x9d. Specifically, the alkylamino group includes, for example, an amino group, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group and a methylethylamino group.
The amino protective group means a normally used protective group, including unlimitedly those substances that can protect the amino group against various reactions. Specifically, the amino protective group includes an acyl group such as a formyl group, an acetyl group and a pivaloyl group; and an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group and a (fluorene-9-yl) methoxycarbonyl group.
The alkoxycarbonyl group includes specifically, for example, methoxycarbonyl group, ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group and a tert-butoxycarbonyl group.
In the description of R1, the term xe2x80x9chaving a substituent(s)xe2x80x9d in the expressions xe2x80x9ca cycloalkyl group having a substituent(s)xe2x80x9d, xe2x80x9ca cycloalkenyl group having a substituent(s)xe2x80x9d and xe2x80x9ca cyclopropyl group having a substituent(s)xe2x80x9d means being substituted with at least one or more substituents, wherein the substituents may be the same or different and a position of the substituent(s) is not specifically limited but may be arbitrarily determined. Specifically, the term includes, for example, a halogen atom, an alkyl group, a substituted alkyl group, a carboxyl group, an alkoxycarbonyl group, a cyano group, an alkylamino group, and an amino group substituted with an amino protective group.
In the description of R4, the term xe2x80x9chaving a substituent(s)xe2x80x9d in the expression xe2x80x9can alkyl group having a substituent(s)xe2x80x9d means being substituted with at least one or more substituents, wherein the substituents may be the same or different and a position of the substituent(s) is not specifically limited but may be arbitrarily determined. Specifically, the term includes, for example, a halogen atom, a hydroxy group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, a cyano group, an alkylamino group, and an amino group substituted with an amino protective group.
In the description of R4, the term xe2x80x9chaving a substituent(s)xe2x80x9d in the expressions xe2x80x9ca cycloalkyl group having a substituent(s)xe2x80x9d and xe2x80x9ca cycloalkenyl group having a substituent(s)xe2x80x9d means being substituted with at least one or more substituents, wherein the substituents may be the same or different and a position of the substituent(s) is not specifically limited but may be arbitrarily determined. Specifically, the term includes, for example, a halogen atom, a hydroxy group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, a cyano group, an alkylamino group, and an amino group substituted with an amino protective group.
In the description of R4, the term xe2x80x9chaving a substituent(s)xe2x80x9d in the expressions xe2x80x9can aryl group having a substituent(s)xe2x80x9d and xe2x80x9can aromatic heterocyclic group having one or more hetero atoms having a substituent(s)xe2x80x9d means having one to three substituents on the ring, wherein the substituents may be the same or different and a position of the substituent(s) is not specifically limited but may be arbitrarily determined. Specifically, the term includes, for example, a halogen atom, an alkyl group, a substituted alkyl group, a hydroxy group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, a cyano group, an alkylamino group, and an amino group substituted with an amino protective group.
The term xe2x80x9cheterocyclic ringxe2x80x9d in the expression xe2x80x9ca heterocyclic ring or a heterocyclic ring having a substituent(s)xe2x80x9d in the description with reference to A and in xe2x80x9ca heterocyclic ring or a heterocyclic ring having a substituent(s)xe2x80x9d in the description with reference to B is used to mean a heterocyclic ring comprising a single ring or two rings with 5 to 7 members consisting of carbon and nitrogen, oxygen, sulfur and so on, and includes specifically, for example, pyridine, dihydropyran, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, pyrazole, furazan, thiadiazole, pyrrolidine, piperidine, piperazine, indole, benzopyrazole, benzoxazole, benzothiazole, benzoimidazole, benzofuran, benzothiophene, pyrazolopyridine, quinoline, isoquinoline, naphthylidine and benzodiazepine. Preferably, the heterocyclic ring should be the one shown in the following diagram, and more preferably pyridine. It is to be noted that for those bonds in both sides with respect to A and B, i.e., the bonds of NR2 and X with A and the bonds X and NR3 with B, the bond positions of them are not limited but may be arbitrarily determined. 
In the above formulas, the first two formulas are preferred.
The term xe2x80x9caromatic heterocyclic ringxe2x80x9d in the expresion xe2x80x9can aromatic heterocyclic ring or an aromatic heterocyclic ring having a substituent(s)xe2x80x9d in the description with reference to A and xe2x80x9can aromatic heterocyclic ring or an aromatic heterocyclic ring having a substituent(s)xe2x80x9d in the description with reference to B represents an unsaturated aromatic heterocyclic ring comprising a single ring or two rings with 5 to 7 members consisting of carbon and nitrogen, oxygen, sulfur and so on, and includes specifically, for example, pyridine, dihydropyran, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, pyrazole, furazan, thiadiazole, indole, benzopyrazole, benzoxazole, benzothiazole, benzoimidazole, benzofuran, benzothiophene, pyrazolopyridine, quinoline, isoquinoline, naphthylidyne and benzodiazepine.
The term xe2x80x9can aromatic ringxe2x80x9d in the expression xe2x80x9can aromatic ring or an aromatic ring having a substituent(s)xe2x80x9d in the description with reference to B represents an aromatic ring comprising a single ring or two rings consisting of carbon atoms, and includes specifically, for example, benzene, naphthalene, indene and naphthalene, wherein benzene is preferable. It is to be noted that the positions of the bonds at both sides with respect to B, i.e., the bonds with X and NR3, are not specifically limited but may be arbitrary determined.
The term xe2x80x9chaving a substituent(s)xe2x80x9d in the expression xe2x80x9ca heterocyclic ring having a substituent(s)xe2x80x9d in the description with reference to A and xe2x80x9can aromatic ring having a substituent(s)xe2x80x9d in the description with reference to B means having one to three substituents on the ring, wherein the substituents may be the same or different and the position of the substituent(s) is not specifically limited but may be arbitrarily determined. Specifically, the term includes, for example, a halogen atom, an alkyl group, a substituted alkyl group, a hydroxy group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, a cyano group, an alkylamino group or an amino group substituted with an amino protective group.
As heterocyclic compounds represented by the general formula (I) in claim 1 and pharmaceutically acceptable salts thereof, the preferred are those wherein B is a phenylene group; R1 is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s); R2 is a hydrogen atom or an alkyl group; R3 is a hydrogen atom or an alkyl group; R4 is an alkyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted or an aromatic heterocyclic ring group which may be substituted and also has one or more hetero atoms; xe2x80x94Xxe2x80x94 is xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHR7xe2x80x94, xe2x80x94CHR8xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CSxe2x80x94, xe2x80x94CSxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Sxe2x80x94CHR9xe2x80x94, xe2x80x94CHR10xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CSxe2x80x94, xe2x80x94CSxe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94NR11xe2x80x94, xe2x80x94NR12xe2x80x94SO2xe2x80x94, xe2x80x94NR13, xe2x80x94NR14xe2x80x94CHR15xe2x80x94, xe2x80x94CHR16xe2x80x94NR17xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90NOR18)xe2x80x94, xe2x80x94C(xe2x95x90CNR19)xe2x80x94, xe2x80x94COxe2x80x94CHR20xe2x80x94, xe2x80x94CHR21xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR22xe2x80x94, xe2x80x94NR23xe2x80x94COxe2x80x94, xe2x80x94CR24R25xe2x80x94, xe2x80x94CHR26xe2x80x94CHR27xe2x80x94 or xe2x80x94CR28xe2x95x90CR29xe2x80x94 wherein R7, R8, R9, R10, R20, R21, R24, R28 and R29 are either of a hydrogen atom or an alkyl group; R11, R12, R13, R14, R17, R18, R9, R22 and R23 are either of a hydrogen atom, an alkyl group or an acyl group; R15 and R16 are a hydrogen atom or an alkyl group; R26 and R27 are either of a hydrogen atom, a hydroxy group or an alkyl group; R25 is a hydrogen atom, an hydroxy group, an alkyl group which may be substituted, a mercapto group, an alkoxy group, an alkylthio group, an acyloxy group, an amino group which may be substituted with an alkyl group or an amino protective group, a carboxyl group, an alkoxycarbonyl group, an aminocarbonyl group, or a cyano group); n is the integer selected from 0 to 6; Y is xe2x80x94C(O)xe2x80x94; and A is an aromatic heterocyclic ring including at least one or more nitrogen atom.
Further, as the heterocyclic compounds represented by the general formula (I) set out in claim 1 or pharmaceutically acceptable salt thereof, the following compounds are preferable.
Preferably, R1 should be a cycloalkyl group having a substituent(s), more preferably a cyclopropyl group having a substituent(s), and most preferably either of a 2,2-dimethylcyclopropyl group, a 2,2-dichlorocyclopropyl group, a 2,2-difluorocyclopropyl group or a 2,2-dibromocyclopropyl group, Among them, 2,2-dimethylcyclopropyl group and 2,2-dichlorocyclopropyl group are especially preferred.
In the case where R1 is a 2,2-dimethylcyclopropyl group having a substituent(s), preferably an absolute configuration of the carbon atom on the cyclopropyl group adjacent to the carbonyl group should be S.
Preferably R2 should be a hydrogen atom or a methyl group, and more preferably hydrogen atom.
Preferably R3 should be a hydrogen atom or a methyl group, and more preferably hydrogen atom.
Preferably R4 should be a cycloalkyl group having a substituent(s) or an aryl group having a substituent(s), more preferably cyclopropyl group having a substituent(s), and most preferably either of a 2,2-dimethylcyclopropyl group, a 2,2-dichlorocyclopropyl group, a 2,2-difluorocyclopropyl group or a 2,2-dibromocyclopropyl group. Further, among them, 2,2-dimethylcyclopropyl group and 2,2-dichlorocyclopropyl group are especially preferred.
In the case where R4 is a 2,2-dimethylcyclopropyl group having a substituent(s), preferably the absolute configuration of the carbon atom on the cyclopropyl group adjacent to the carbonyl group should be S.
Further, in the case where each of R1 and R4 is a 2,2-dimethylcyclopropyl group having a substituent(s), preferably the absolute configuration of the carbon atoms on the cyclopropyl group of R1 adjacent to the carbonyl group should be S for both.
Preferably, A should be either of an aromatic heterocyclic ring or an aromatic heterocyclic ring having a substituent(s), and more preferably either of a pyridine, a pyridazine, a pyrimidine, a pyridine having a substituent(s), a pyridazine having a substituent(s) or a pyrimidine having a substituent(s).
Preferably, B should be either of an aromatic ring, an aromatic ring having a substituent(s), an aromatic heterocyclic ring or an aromatic heterocyclic ring having a substituent(s), and more preferably a benzene ring or a benzene ring having a substituent(s).
Preferably, X should be an interatomic bond, xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHR7xe2x80x94, xe2x80x94CHR8xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR3, xe2x80x94CR24R25xe2x80x94 or xe2x80x94Oxe2x80x94CHR30xe2x80x94CHR31xe2x80x94 wherin R7, R8, R24, R30 and R31 are either of a hydrogen atom or an alkyl group; R13 is either of a hydrogen atom, an alkyl group or an acyl group; and R25 is a hydrogen atom, a hydroxy group, an alkyl group, an alkyl group having a substituent(s), a mercapto group, an alkoxy group, an alkylthio group, an acyloxy group, an amino group, an alkylamino group, an amino group substituted with an amino protective group, a carboxyl group, an alkoxycarbonyl group, an aminocarbonyl group, or a cyano group); and more preferably xe2x80x94Xxe2x80x94 should be xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHR7xe2x80x94, xe2x80x94CHR8xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR13xe2x80x94 or xe2x80x94CR24R25xe2x80x94 wherein R7, R8 and R24 are either of a hydrogen atom or an alkyl group; R13 is either of a hydrogen atom, an alkyl group or an acyl group; and R25 is a hydrogen atom, a hydroxy group, an alkyl group which may be substituted, a mercapto group, an alkoxy group, an alkylthio group, an acyloxy group, an amino group which may be substituted with an alkyl group or an amino protective group, a carboxyl group, an alkoxycarbonyl group, an aminocarbonyl group, or a cyano group.
Preferably, Y should be an interatomic bond, xe2x80x94COxe2x80x94, xe2x80x94CONR5xe2x80x94, xe2x80x94CSNR6xe2x80x94 or xe2x80x94SO2xe2x80x94 wherein R5 a R6 are a hydrogen atom or an alkyl group, and more preferably Y should be xe2x80x94COxe2x80x94.
Further, in the present invention, R1 and R4 may be the same or different from each other, which may be either of a 2,2-dimethylcyclopropyl group, a 2,2-dichlorocyclopropyl group, a 2,2-difluorocyclopropyl group or a 2,2-dibromocyclopropyl group, and preferably xe2x80x94Yxe2x80x94 should be xe2x80x94Oxe2x80x94 and n=0.
Further in the present invention, preferably R1 should be either of a 2,2-dimethylcyclopropyl group, a 2,2-dichlorocyclopropyl group, a2,2-difluorocyclopropyl group or a 2,2-dibromolcyclopropyl group; R4 should be an aryl group or an aryl group having a substituent(s);xe2x80x94Yxe2x80x94 should be the xe2x80x94COxe2x80x94; and n should be an integer selected from 1 to 3.
Further in the present invention, preferably R1 should be either of a 2,2-dimethylcyclopropyl group, a 2,2-dichlorocyclopropyl group, a2,2-difluorocyclopropyl group or a 2,2-dibromocyclopropyl group; R4 should be an aryl group or an aryl group having a substituent(s); xe2x80x94Yxe2x80x94 should be an interatomic bond, and n should be an integer selected from 2 to 4.
Further in the present invention, a heterocyclic compound or a pharmaceutically acceptable salt thereof represented by any of the following formulas is preferred. 
The pharmaceutically acceptable salt includes, for a sufficiently acidic compound according to the present invention, for example, an ammonium salt, an alkali metal salt (for example, a sodium salt and a potassium salt which are preferable) and an alkali earth metal salt (for example, a calcium salt and a magnesium salt which are preferable) of the compound, and for a salt of organic bases, for example, a dicyclohexylamine salt, a benzathine salt, a N-methyl-D-glucan salt, a hydramine salt and a salt of amino acid such as arginine or lysine. Further, for a sufficiently basic compound according to the present invention, the pharmaceutically acceptable salt specifically includes an acid added salt of the compound, for example, an inorganic acid salt such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, or an organic acid salt such as acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid and monomethylsulfate. Further, depending on the case, the salt may includes a salt hydrate or a hydrate.
It is to be noted that the present invention should include all of the isomers such as an optical isomer and a geometric isomer, a hydrate, a solvate or a crystal form.
The compounds of the present invention can be synthesized by way of the following method.
For example, compounds of the present invention defined in (I) wherein X is an oxygen atom, Y is a carbonyl group, n=0, A is pyridine, B is benzene and R1 and R4 are the same, can be obtained by reacting corresponding diamine compounds with corresponding acid halide such as an acid chloride by 2 or more equivalents in the presence of base, or otherwise may be reacted with carboxylic acid by 2 or more equivalents in the presence of the condensation agent, as shown below, thereby obtaining the intended compound. 
wherein R is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s), and the Z is a halogen atom.
Further, by using the reaction shown above with small modification applied thereto, it will be also possible to synthesize a compound wherein X is a nitrogen atom or a sulfur atom, a compound wherein A is a heterocyclic ring other than pyridine, or a compound wherein B is an aromatic or a heterocyclic ring other than benzene ring.
For example, compounds of present invention defined in (I) wherein X is a carbon atom, Y is a carbonyl group, n=0, A is a pyridine, B is a benzene and R1 and R4 are the same, can be obtained by reacting corresponding diamine compounds with corresponding acid halide such as an acid chloride by 2 or more equivalents in the presence of base, or otherwise may be reacted with a carboxylic acid by 2 or more equivalents in the presence of a condensation agent, leading to a ketone body, which will be further reduced to an alcohol compound and the alcohol compound will be further reduced so as to synthesize a methylene body, as shown below. 
wherein R is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s), and Z is a halogen atom.
Further, in the above reactions, a compound having different amide substituents at opposite ends can be synthesized by introducing sequentially the amide substituents by way of, for example, changing the sequence of the procedures after (XI) so that hydrolyzing may be practiced first to generate an amine compound, which will be precedently acylated.
For example, compounds of the present invention defined in (I) wherein xe2x80x94Xxe2x80x94 is xe2x80x94OCH2xe2x80x94, Y is a carbonyl group, n=0, A is pyridine, B is benzene, and R1 and R4 are the same, can be obtained by reacting corresponding diamine compounds with corresponding acid halide such as an acid chloride by 2 or more equivalents in the presence of base, or otherwise may be reacted with a carboxylic acid by 2 or more equivalents in the presence of a condensation agent, thereby obtaining the objective compound, as shown below. 
wherein R is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s), X is a leaving group such as a halogen atom and Z is a halogen atom.
Further, by using the reaction shown above with small modification applied thereto, a compound wherein X is xe2x80x94OCH2CH2CH2xe2x80x94 or xe2x80x94SCH2xe2x80x94 can be synthesized For example, compounds of the present invention defined in (I) wherein xe2x80x94Xxe2x80x94 is xe2x80x94CH2xe2x80x94, Y is a carbonyl group, n=0, A is a thiazole, B is benzene, and R1 and R4 are the same, can be obtained by reacting corresponding diamine compounds with corresponding acid halide such as an acid chloride by 2 or more equivalents in the presence of base, or otherwise may be reacted with a carboxylic acid by 2 or more equivalents in the presence of the condensation agent, thereby obtaining the objective compound, as shown below. 
wherein R is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s), and Z is a halogen atom.
For example, compounds of present invention defined in (I) wherein xe2x80x94Xxe2x80x94 is xe2x80x94CH2xe2x80x94, Y is a carbonyl group, n=0, A is piperidine, B is benzene, and R1 and R4 are the same, can be obtained by reacting corresponding diamine compounds with corresponding acid halide such as an acid chloride by 2 or more equivalents in the presence of base, or otherwise may be reacted with a carboxylic acid by 2 or more equivalents in the presence of the condensation agent, thereby obtaining the objective compound, as shown below. 
wherein R is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s), X is a leaving group such as a halogen atom and Z is a halogen atom.
Further, by using the reaction shown above with small modification applied thereto, a compound wherein X of xe2x80x94CH2CH2xe2x80x94 can be synthesized.
For example, compounds of the present invention defined in (I) wherein xe2x80x94Xxe2x80x94 is an oxygen atom, Y is a carbonyl group, n=0, A is pyridine, B is benzene, and R1 and R4 are different from each other, can be obtained by reacting, corresponding diamine compounds with corresponding acid halide such as an acid chloride by about one equivalent in the presence of base, or otherwise may be reacted with a carboxylic acid by about one equivalent in the presence of the condensation agent, thereby introducing a substituent(s) to one end of the diamine compound, and similarly the resultant compound may be additionally reacted with the acid halide or the carboxylic acid having a structure different from that of the acid halide or the carboxylic acid which has been used in the preceding stage so as to obtain the objective compound, as shown below. 
wherein R1 is an alkyl group, an alkyl group having a substituent(s), a cycloalkyl group, a cycloalkyl group having a substituent(s), a cycloalkenyl group, a cycloalkenyl group having a substituent(s), an aryl group, an aryl group having a substituent(s), a heterocyclic ring having one or more hetero atoms or a heterocyclic ring having one or more hetero atoms and a substituent(s); R2 is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s); and Z is a halogen atom.
Further, a compound having R1 different from R4 can be synthesized by, for example, introducing an acyl group in incremental steps according to an alternative method as shown below. 
wherein R1 is an alkyl group, an alkyl group having a substituent(s), a cycloalkyl group, a cycloalkyl group having a substituent(s), a cycloalkenyl group, a cycloalkenyl group having a substituent(s), an aryl group, an aryl group having a substituent(s), a heterocyclic ring having one or more hetero atoms or a heterocyclic ring having one or more hetero atoms and a substituent(s); R2 is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s); and Z is a halogen atom.
Further, a compound having R1 different from R4 can be synthesized also using such a method in which a substituent(s) for R1 may be introduced at the last stage by elaborating an amine protector as an intermediate, as shown below. 
wherein R1 is an alkyl group, an alkyl group having a substituent(s), a cycloalkyl group, a cycloalkyl group having a substituent(s), a cycloalkenyl group, a cycloalkenyl group having a substituent(s), an aryl group, an aryl group having a substituent(s), a heterocyclic ring having one or more hetero atoms or a heterocyclic ring having one or more hetero atoms and a substituent(s); R2 is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s); Z is a halogen atom; and P is an amino protective group.
For example, compounds of the present invention defined in (I) wherein X is an oxygen atom, Y is an interatomic bond, n=2, A is a pyridine and B is a benzene, can be obtained by reacting monoamide compounds with corresponding alkylating agent such as an alkyl halide in the presence of base, as shown below, thereby obtaining the objective compound. 
wherein R1 is an alkyl group, an alkyl group having a substituent(s), a cycloalkyl group, a cycloalkyl group having a substituent(s), a cycloalkenyl group, a cycloalkenyl group having a substituent(s), an aryl group, an aryl group having a substituent(s), a heterocyclic ring having one or more hetero atoms, or a heterocyclic ring having one or more hetero atoms and a substituent(s); and R2 is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s).
To synthesize, for example, the compounds of the present invention defined in (I) wherein X is an oxygen atom, xe2x80x94Yxe2x80x94 is xe2x80x94CONHxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94COOxe2x80x94, n=0, A is a pyridine and B is a benzene, for example, monoamide compounds may be used as a starting material, and then they may be reacted respectively with the corresponding isocyanate, sulfonyl halide, or ester chlorocarbonate, as shown below, thereby obtaining the objective compound. 
wherein R1 is an alkyl group, an alkyl group having a substituent(s), a cycloalkyl group, a cycloalkyl group having a substituent(s), a cycloalkenyl group, a cycloalkenyl group having a substituent(s), an aryl group, an aryl group having a substituent(s), a heterocyclic ring having one or more hetero atoms, or a heterocyclic ring having one or more hetero atoms and a substituent(s); and R2 is a cycloalkyl group having a substituent(s) or a cycloalkenyl group having a substituent(s).
Further, by using a reaction similar to the aforementioned reaction, a compound having xe2x80x94Yxe2x80x94 of xe2x80x94CSNHxe2x80x94 or xe2x80x94SOxe2x80x94 may be synthesized.
It should be appreciated that those compounds of the present invention obtainable by the methods defined above can be refined by using the known technologies, including the extraction, distillation, crystallization or column chromatography, which have been normally used in the organic synthesis.
Those obtained compounds of the present invention, as will be described later, have an activity for inhibiting the AP-1 or NF-kappaB activation and thus are useful in providing the cure against the inflammatory diseases which might be developed by those transcription factors. That is, the compounds of the present invention are useful as an anti-inflammatory agent, an anti-rheumatism agent, an immunosuppressive agent, a cancer metastasis inhibitor, an antiviral agent or a curative agent for arterial sclerosis, advantageously without side effects such as hormone action, which can inhibit the transcription of genes of a plurality of inflammatory cytokines, matrix metalloproteases, inflammatory cell adhesion factors, and so on.
If the compound of the present invention is used as a drug such as the anti-inflammatory agent, it may be administered in the manners of an oral administration, an intravenous administration, a percutaneous administration and an administration by way of eye-instillation. A dosage should be different depending on the symptom, an age of a patient and the applied administration method, typically 1xcx9c3000 mg/kg/day.
The compound of the present invention can be formulated by the conventional method. The compound can be formulated as a drug product in the forms of, for example, an injection, a tablet, a granule, a fine granule, a powder, a capsule, a cream, a suppository and the like, wherein those formulation carriers are available for the drug product, including, for example, lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, amylum, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, ethanol, carboxymethylcellulose, carboxymethyl cellulose calcium salt, magnesium stearate, talc, acetyl cellulose, saccharose, titanium oxide, benzoic acid, p-oxybenzoate ester, sodium dehydro acetate, gum arabic, tragacanth, methylcellulose, egg york, surfactant, sucrose, simple syrup, citric acid, distilled water, ethanol, glycerin, propylene glycol, macrogol, sodium monohydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, dextrose, sodium chloride, phenol, thimerosal, p-oxybenzoic ester and sodium hydrogensulfite, which will be mixed with the compound of the present invention in use depending on the form of the drug product.
Further, a content of an active constituent included in the drug product of the present invention may be varied in dependence on the form of the drug product and not specifically limited but typically in the range of 0.01xcx9c100 weight percent, preferably in the range of 1xcx9c100 weight percent.
The present invention will now be described in more detail with reference to examples, though the present invention is not limited to those.